A functional role of Cdx2 in beta-catenin signaling during transdifferentiation in endometrial carcinomas.

Nuclear beta-catenin is required for changes in morphology from glandular to morular phenotypes of endometrial carcinoma (Em Ca) cells, with activation of p14(ARF)/p53/p21(Waf1) and alteration of p16(INK4A)/pRb pathways. Having demonstrated previously that the homeodomain transcription factor Cdx2 increases markedly during intestinal epithelial cell differentiation, we have examined its effects in beta-catenin signaling during transdifferentiation of Em Ca cells. In clinical cases, Cdx2 immunoreactivity, along with increased mRNA signals, was found to overlap with nuclear accumulation of beta-catenin and p21(Waf1) in morules, demonstrating an inverse correlation with cell proliferation. In cell lines, over-expression of active form beta-catenin resulted in a significant increase in endogenous Cdx2 expression at both mRNA and protein levels. Furthermore, the Cdx2 promoter was activated by T-cell factor 4 (TCF4) -independent activated beta-catenin, as well as Cdx2 itself, through the region from -39 to +9 bp relative to transcription start site. Cells over-expressing exogenous Cdx2 showed high levels of p21(Waf1) expression due to stabilization of the mRNA status, resulting in significant decrease in the proliferation rate, in contrast to the lack of apparent changes in morphology. Moreover, transfected Cdx2 could inhibit beta-catenin/TCF4-mediated transcriptional activation of target genes, including p14(ARF) and cyclin D1, probably through indirect mechanisms. These data suggest that over-expression of Cdx2 mediated by nuclear beta-catenin and Cdx2 itself can cause an inhibition of Em Ca cell proliferation through up-regulation of p21(Waf1) expression, modulating beta-catenin/TCF4-mediated transcription. We therefore conclude that an association between Cdx2 and beta-catenin signaling may participate in induction of transdifferentiation of Em Ca cells.